Lysosomal Storage Disease Flashcards
What are lysosomes?
Lysosomes are subcellular organelles involved in the degradation of complex lipids, glycosaminoglycans, and glycogen.
Generally, the deficiency of a specific lysosomal enzyme involved in the catabolism of the compounds results in lysosomal storage disorders (LSD)
Whhat is the significancw of lysosomal enzym3s?
- Lysosomal enzymes are active at an acidic pH (pH 5)
- They are involved in the degradation of glycosaminoglycans (mucopolysaccharides), sphingolipids (glycolipids and sphingophospholipids) and glycogen.
- These enzymes remove one sugar unit at a time from these molecules
• A specific enzyme of the degradative pathway is deficient in these
disorders, resulting in accumulation of the substrate of the pathway
- The rate of biosynthesis of the compound is usually normal, but the rate of lysosomal degradation is slow due to inherited deficiency of the lysosomal enzyme
- The substrate of the deficient enzyme accumulates in the lysosomes, resulting in swelling of the lysosomes and consequent organ damage>
What are the common features of lysosomal storage diseases?
- Most of the disorders are autosomal recessive disorders
- Commonly affect infants and young children
• Storage of insoluble intermediates in the mononuclear phagocyte system, giving rise to hepatosplenomegaly
• Frequent CNS involvement with associated neuronal damage
• Cellular dysfunctions, caused by
– Storage of undigested material
– And as a result of macrophage activation and release of cytokines
• Confirmation of diagnosis by assay of the specific enzyme in
leucocytes or skin fibroblasts>
What are the lysosomal storage diseases?
• Mucopolysaccharidoses
– Hurlersyndrome
– Hunter syndrome
• Sphingolipidoses – Tay-Sachsdisease – Gauchersdisease – Fabrydisease – Niemann-Pickdisease(sphingophospholipid) – Metachromatic leukodystrophy
• Glycogen storage disease (Pompe’s disease, GSD II)
• I-cell disease
For each of the disorder listed above – Identify the compound accumulated and the biochemical defect (enzyme), clinical features, cell morphology>
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What are the mucopolysaccharides?
- Characterized by a deficiency of an enzyme required for the lysosomal degradation of glycosaminoglycans (mucopolysaccharides)
- The glycosaminoglycans are degraded in the lysosomes by the removal of one sugar unit at a time
- Hurler syndrome and Hunter syndromes are characterized by accumulation of dermatan sulfate and heparan sulfate (glycosaminoglycans)
• Enzyme replacement therapy with the specific enzyme has been tried in both the disorders with varied success (Does not cross
BBB)
What is the hurler syndrome?
- Enzyme deficient: Iduronidase
- Substrates accumulating: Dermatan sulfate and heparan sulfate
- Urine is positive for glycosaminoglycans
- Fibroblast assay for the deficient enzyme is diagnostic
- Enzyme replacement therapy with iduronidase has been successful in many patients
- Hurler > Hurler-Scheie > Scheie
What is hunter syndrome?
Milder form
• X-linkedrecessive(affectsmales
predominantly)
• Enzyme deficient: Iduronate sulfatase
- Coarse facial features, hepatosplenomegaly, mild to moderate developmental delay, but NO corneal clouding
- Hematopoieticstemcelltherapy
- Enzyme replacement study Jan 2014 suggests improvement in mobility, liver and spleen volumes reduced>
What is sphingolipidoses?
- Sphingolipids are a group of complex lipids containing sphingosine as the alcohol (not glycerol)
- Sphingosine + Fatty acid = Ceramide esterified
• Sphingolipids are of two classes
– Glycosphingolipids/glycolipid
– containing a carbohydrate
moiety linked to ceramide
– Sphingophospholipids that contain a phosphoryl choline moiety linked to ceramide (e.g. sphingomyelin
What is Tay-Sachs disease?
- Deficient enzyme: β-Hexosaminidase A
- Accumulating substrate: Ganglioside (GM2). Also known as gangliosidosis
- Progressive neurodegeneration after the age of 3-6 months, blindness
- Developmental milestone delay often regression (child not able to sit or stand in the later stages)
- Generally fatal by 2-6 years
Describe heterozygous tay sachs
- Carriers (heterozygotes) have one copy of the mutant gene and one copy of the normal gene
- Carriers can be detected by enzyme assays – they have about 50% hexosaminidase activity compared to normal controls – Carriers are phenotypically normal and have no manifestations
What is Gaucher disease?
- Most common lysosomal storage disorder
- Deficient enzyme: β-Glucosidase
- Accumulating substrate: Glucosyl ceramide (aka glucocerebroside)
- Macrophages engorged with glucocerebrosides
- Adult form (most common) shows no neurological damage but marked hepatosplenomegaly and osteoporosis of long bones
• “Bone Crisis” is often when adults first come to clinic
Glucosyl ceramide
• Enzyme replacement therapy is used in many patients with Gaucher disease >
What is Fabry disease?
• X-linked recessive disorder (Males commonly affected)
• Deficient enzyme: -Galactosidase
• Accumulating substrate: Globoside
(aka ceramide trihexoside)
• Peripheral neuropathy (tingling and burning of extremities, “acroparesthesias”
Whhat is the phenotype of fabry disease?
- Globoside accumulates in the blood vessels of skin, kidneys, nerves and heart
- Many children may have life threatening complications like kidney damage, heart attack and stroke
- Carrier females can show mild clinical feature
What is Niemann-Pick disease?
• Deficientenzyme:Sphingomyelinase
• Accumulatingsubstrate:
Sphingomyelin (sphingophospholipid)
• Accumulation of sphingomyelin in the
neuronal tissues
• Type A is a severe infantile form
– Fatal by 2-3 years
– Cherry-red spot in macula on retinal examination (blindness)
• Type B appears later in childhood, presents with hepatosplenomegaly
What is metachromatic leukodystrophy?
• Deficient enzyme: Aryl Sulfatase A
• Accumulating substrate: Sulfatide
(rich in neurons)
• Progressive paralysis and demyelination
What is pompe disease?
- A small amount of cellular glycogen is degraded by the lysosomal acid maltase (1→4 glucosidase)
- Generalized accumulation of glycogen in heart, muscle, kidney and liver as vacuoles in the lysosomes (glycogen storage disorder type II)
- Enzyme replacement therapy has been successful
• Glycogenaccumulationinthe
– Cardiac muscle can result in death due to cardiac failure
– Skeletal muscle can result in myopathy
– Liver can result in hepatocellular damage
Explain the trafficking of enzymes to the lysosomes?
- Enzymes synthesized in the ER are transported to the Golgi apparatus
- In the Golgi apparatus, there is phosphorylation of mannose to form mannose-6-phosphate
- Enzymes that have a mannose-6-P are transported to the lysosomes
- Enzymes/proteins without the mannose-6-P are secreted by the cell
What is inclusion cell disease( I-cell disease)?
Children with the disease have a defect in trafficking enzymes to the lysosomes
- The Golgi fails to add the mannose-6-P marker to the enzymes destined for the lysosomes
- These enzymes (without the mannose-6-P marker) are secreted into the blood stream. An associated finding in these patients is the presence of high concentration of lysosomal enzymes in the blood
- There is a deficiency of many lysosomal enzymes, and there is accumulation of glycosaminoglycans and sphingolipids in the lysosomes
- An unique feature of this disease is the presence of intracytoplasmic inclusions in the fibroblasts of patients. These cells are termed ‘inclusion cells’, or ‘I-cells’ >
What Mnemonics are used in lysosomes?
- They’re all autosomal recessive, with the exception of Fabry’s and Hunter’s, which are both X-linked recessive.
- Hurler and Hunter’s both start with an H, and both accumulate Heparan sulfate. (Hopefully that will help you remember that they accumulate Dermatan sulfate too).
- Ashkenazi Jews have a higher risk of Gaucher’s, Niemann-Pick, and Tay-Sachs.
- Gaucher’s spares the Brain., has crumpled tissue paper appearance.
- “Cherry-Red” (spot on macula) is hyphenated. So are “Niemann-Pick” and “Tay-Sachs.” :)
- Hunters is X-linked. I view a Hunter shooting his bow at a X (target).
- Niemann-Picks - Sphingomyelinase. No man picks his nose with his Sphinger (finger).
- As above regarding Hunter’s vs Hurlers. Hurlers you get corneal clouding, so you cannot be a good hunter.
- HurLer’s is alpha-L-iduronidase. Hunters, which is a similar disease, is the other one (iduronate sulfatase). “I just remember one, then know that the other one is the other one.”
- Metachromatic Leukodystrophy : Arysulfatase A deficiency
- One way to remember Iduronidase is that it has two D’s and its a hur-dle to pronounce
